Di-hydro-s-triazines

ABSTRACT

Anti-malarial and anti-bacterial compounds and compositions are provided which are N-substituted symmetrical dihydro triazines or salts represented by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2ethoxy-5-chlorobenzyloxy)-1,3,5 -triazine hydrochloride. The compounds can be prepared by reacting a substituted diguanide with a carbonyl compound in the presence of a strong acid and then salifying or acylating the reaction product.

United States Patent Mamalis 1 May 30, 1972 [5 DI-HYDRO-S-TRIAZINES Rences Cited 72] inventor: Patrick Mamaiis, Reigate, England UNITEDSTATES PATENTS 2 976 288 3/1961 Green et ai. ..260/249.9 3 Beech GLimited 8 ti d, E [7 Ass'gnee gland mp 3,105,074 9/1963 Mamaiis..260/249.9 [22] Filed: Dec. 5, 1969 Primary Examiner-John M. Ford [211pp No I 882 724 Anomey-JacobsJzJacobs [57] ABSTRACT [30] Foreign AppumdoPriority Data Anti-malarial and anti-bacterial compounds andcompositions Dec. 20, 1968 Great Britain ...60,848/69 are Provided whichare N-subslimted symmetrical dihydro triazines or salts represented by4,6-diamino-i,2-dihydro-2,2- dimethyii 2-ethoxy-5-chlorobenzyloxy)- l,3,$-triazine ..2 fi g 56;: hydrochloride. The compounds can be preparedby reacting a [58] Fieid fl 260/249 9 substituted diguanide with acarbonyl compound in the presence of a strong acid and then salifying oracyiating the reaction product.

9Ciaims,NoDravvings where Ar is: an aryl ring system which issubstituted by at least one alkoxy group of one 24 carbon atoms and atleast one halogen atom or which is substituted-by at least onehalogenoloweralkyl group of one six carbon atoms,

R is:

hydrogen or lower alkyl of one four carbon atoms R is:

lower alkyl of one four carbon atoms where R and R may be the same ordifferent and may be joined to each other to fonn a spirocycloalkanegroup or a lower alkyl spirocycloalkane group including the 2-carbonatom of the triazine ring, the spirocycloalkane group having five sevencarbon atoms, and acid addition salts thereof.

Preferably Ar is a substituted benzene ring.

In one preferred group of compounds of the invention Ar may besubstituted by a single alkoxy group and by a single halogen atom. Thealkoxy group conveniently contains one six carbon atoms and the halogenis chlorine or bromine.

ln an especially preferred group of compounds Ar is benzene with analkoxy group in the 2-position and a halogen atom in the 5-position.

In another preferred group of compounds of the invention Ar may besubstituted by a single halogenoloweralkyl group. The lower alkyl groupmay be straight chain or branched and may be substituted by one or morehalogen atoms. A preferred group is the trifluoromethyl group.

The groups R, and R are conveniently both methyl.

Other substituents may also be present, for example nitro or loweralkoxycarbonyl groups, the lower alkoxy part having one six carbon atoms.

Although formulas have been used herein in order to represent thecompounds of the present invention, the nature and value of the presentinvention does not depend upon the precise theoretical correctness ofthese formulas. The names and formulas used herein are not intended tolimit the invention to any specific tautorneric form or to any specificoptical or geometric isomer.

Structures of the following form may for example contribute towardsFormula I N N HEN-f W=NH HN=f W=NH AICHz-ON N Thus the compounds of thepresent invention may be made in the form of the monohydrohalic acidaddition salts for example the hydrobromide or the hydrochloride. Othersalts may be made however and may be desirable in order to modify theproperties of the product such as its toxicity, taste or physical form.For example the compounds may be made in the form of the picrate,saccharinate, acetate, acid maleate, acid phthalate, succinate,phosphate, p-nitrobenzoate, stearate, mandelate, N-acetylglycinate,pamoate, cyclamate, citrate, tanrate, cyclohexylsulpharnate orgluconate.

The presence of the amino groups on the triazjne ring of formula lcreates the possibility of forming acyl derivatives by reaction withacylating agents for example acyl halides and anhydride's. One to fouracetyl groups for example may be associated with the compound of FormulaI. The present invention therefore includes compounds of Fonnula l inthe fonn of acyl derivatives (e.g., an acetyl derivative).

Compounds within the scope of the present invention have activityagainst bacteria, parasites, including the Plasmodia of malaria, fungiincluding dermatophytes and Candida.

Thus activity has been observed against Staph. a ureus, Esch. coli,Candida albicans, Prat. mirabilis, Pseudomonas pycyanea, Strep.haemolyticus.

For example 4,6-diarninol ,2-dihydro-2,2-dimethyll 2-nbutoxy-5-bromobenzyloxy)-l,3,5-triazine hydrochloride of formula H C land its 3-trifluoromethylbenzyloxy analogue display activity againstPlasmodium berghei in the mouse.

The present invention also provides a process for the preparation of thecompounds of the present invention which comprises reacting a diguanideof general formula with a carbonyl compound of general formula in thepresence of an acid where R is Ar or a group capable of conversionthereto and converting R; where necessary into Ar and optionally forminga salt or acyl derivative. Preferably the acid is a strong acid forexample hydrochloric or formic.

The reaction may in some cases be carried out without any furthersolvents or diluents, but usually an inert solvent, such as a loweraliphatic alcohol, (e.g., methanol), is preferred. Preferably at leastone molecular equivalent of acid is used.

If R is Ar the desired product is obtained in one stage.

Alternatively, the group R may be chosen so as to be convertible intothe group Ar. For example R CH may be a group R which is subjected tocatalytic hydrogenolysis after the formation of an R ON substitutedtriazine to produce the hydroxy triazine lll R1 R2 Ill R, may forexample be substituted or unsubstituted benzyl or substituted orunsubstituted naphthylmethyl, and the hydrogenolysis may be carried outwith hydrogen in the presence of a palladium catalyst.

The hydroxytriazine lll may then be reacted in a variety of ways wellunderstood by those skilled in the art to produce the desiredsubstituted triazine of Formula I.

Thus well-known ether-forming synthetic methods may be used to link theside-chain to the triazine with the atom previously in place on either.Typical examples are l. the reaction of a halide with a hydroxy!compound with or without added base 2. the reaction of a reactive estersuch as a sulphonate with a hydroxy] compound.

The final product will usually be obtained in the form of an acidaddition salt as a consequence of the reaction but if necessary theadditional step of reacting the free base with an acid to form a saltmay be performed. Salts can be converted back to the free base bytreatment with alkali (e.g., KOH) and then converted to other salts asrequired by conventional means.

A further aspect of the present invention provides a process for thepreparation of the compounds of the present invention which comprisesreacting a triazine N mN-f Warm where Y, is a reactive group with acompound R Y where R -,Y is a group capable of reacting with Y, so as toconvert Y, into Ar CH O or into a group capable of conversion into Ar CH0.

Preferably Y, and Y, are OH or derivatives of OH capable of reactingwith each other to form an oxygen linkage. Thus Y and Y, should have atleast one oxygen atom between them. Conveniently Y, is OH or OM where Mis an alkali metal and Y is chlorine, bromine or iodine. Other reactivederivatives of the OH group include sulphonic acid derivatrves.

[n a preferred process a compound Ar CH Z where Z is chlorine or bromineis reacted with the hydroxy triazine ill in an inert solvent or diluent.Examples of suitable solvents include dimethyl sulphoxide,dimethylformamide or ethanol.

The hydroxy triazine derivative III is usually obtained in the form ofan acid addition salt (e.g., the hydrochloride) from which the free basemay be liberated by one equivalent of base such as an alkali metalhydroxide (e.g., potassium hydroxide) or sodium in ethanol or methanol.The mixture may then be evaporated and reacted in a suitable solvent(e.g., dimethylforrnamide 0r dimethylsulphoxide). Preferably extra baseis not added, since with two equivalents of sodium in alcohol forexample a less pure product is obtained.

In a modified procedure, usually giving poorer yields, the hydrochlorideof compound Ill in dimethyl formamide or dimethylsulphoxide is reactedwith one equivalent of aqueous potassium hydroxide (using as littlewater as possible) and the resulting mixture reacted to give a triazinehydrohalide.

The Y, Nsubstituted triazine lV may be made from an appropn'atelysubstituted diguanide as outlined above or otherwise.

The present invention also provides pharmaceutical compositions for useagainst malaria comprising as active ingredient a compound according tothe present invention together with a pharmaceutically acceptablecarrier.

Thus the active compounds of this invention may be employed for thetreatment of malaria. Therefore, one aspect of the present invention isa method of treatment of malaria which comprises administering one ofthe active compounds. The compound may be administered orally,parenterally or by suppository, though the oral route is preferred.

The dose of the compound needed will, of course, depend on theparticular salt form used, the route of presentation and whether thecompound is being used as a prophylactic or as a therapeutic dose togive clinical or radical cure of the disease.

As stated above the compound of this invention may be administeredorally, parenterally or by suppository. The water solubility of thehydrochloride of the compound and most other salts is low and thehydrochloride is non-hygroscopic. lf solutions are required it will benecessary to add solubilizing agents to the water, choose non-aqueoussolvents, find a more soluble salt or prepare very dilute solutions.

Oral formulations are preferred and with the above proviso in connectionwith solutions, typical oral formulations will include tablets, pills,capsules, sachets, granules, powders, chewing gum, suspensions,emulsions and solutions: particularly preferred oral formulations aretablets and capsules. Where appropriate and where necessary theformulations may include diluents, binding agents, dispersing agents,surface-active agents, lubricating agents, coating materials, flavoringagents, coloring agents, solvents, thickening agents, suspending agents,sweeteners or any other pharmaceutically acceptable additives, forexample gelatin, lactose, starch, talc, magnesium stearate, hydrogenatedoils, polyglycols and syrups. Where the formulations are tablets orcapsules and the like they will represent pre-measured unit doses but inthe case of granules, powders, suspensions and the like the formulationsmay be presented as pre-measured unit doses or in multi-dose containersfrom which the appropriate unit dose may be withdrawn.

The injectable form may be an aqueous or non-aqueous solution,suspension, or emulsion in a pharmaceutically acceptable liquid (e.g.,sterile pyrogen-free water or parenterally acceptable oils) or mixtureof liquids which may contain bacteriostatic agents, antioxidants orother preservatives, buffers (preferably in the physiological pH rangeof 6.5 7.0), solutes to render the solution isotonic with the blood,thickening agents, suspending agents or other pharrnaceuticallyacceptable additives. Such forms will be presented in unit dose formsuch as ampules or disposable injection devices, or in multidose fonnssuch as a bottle from which the appropriate dose may be withdrawn, or asa solid form or concentrate which can be used to quickly prepare aninjectable formulation. All formulations for injections are preferablyrendered sterile. Suppositories containing the compound will alsocontain suitable carriers, e. g., cocoa butter or polyglycols).

In addition to standard pharmaceutical additives, there may be includedwithin formulations of the compound other therapeutic agents,particularly including other antimalarials (e.g., sulphonamides).

Insofar as the formulations of the present invention are novel thisinvention also provides a method of producing them.

Examples of the invention will now be described.

EXAMPLE 1 4,6-Diarninol ,2-dihydro-2,2-dimethyll Z-n-butoxy-S-bromobenzyloxy l ,3,5-triazine hydrochloride p-Bromo-n-butoxybenzene(22.9 g.) paraformaldehyde (5g.), anhydrous EnCL (5 g.) all dissolved indry GHQ, (50 ml), were treated with dry KCl gas for 1 hour at 40 50 C.The mixture was then stirred at this temperature for 3 hours. Thereaction mixture was washed with water, dried and the solventevaporated. The residue was distilled at 0.05 mm. and the fractionboiling at 1 l0 1 14 C collected and identified as2-n-butoxy-5-bromobenzyl chloride (9.2 g. n 1.5520, Lt. 1.5546).

4,6-Diamino-l ,2-dihydro-2,2-dimethyll-hydroxy- 1 ,3,5- triazinehydrochloride (6.27 g.) was dissolved in MeOH (50 ml.) and a solution ofKOH (2.14 g.) in NeOH (50 ml.) added. The mixture was refluxed for 20minutes, and the solvent removed in vacuo. The residual solid wassuspended in DMF and the 2-n-butoxy-5-bromobenzyl chloride (9.0 g.)added. The mixture was stirred at room temperature for 16 hours, theprecipitated inorganic solid was removed by filtration and the solventevaporated under vacuum.

The residue was triturated with acetone to give a white solid, which waswashed with water and dried, 11.7 g. m.p. 207 209. A small amount wasrecrystallized from Ethanol/Ether, m.p. 208 210. The analysis wascorrect for 4,6-diaminol ,2-dihydro-2,2-dimethyll 2-n-butoxy-5-bromobenzyloxy)- l ,3,5-triazine hydrochloride.

EXAMPLE 2 EXAMPLES 3 7 The compounds were in the form of thehydrochloride in all examples, and were made by processes closelysimilar to those described in Examples 1 and 2.

FORMULA 1 Example Number Ar R, R m.p.C

3 Z-methoxy-S-bromophenyl -(CHz)s- 214-216 4 2-ethoxy-5-bromcphenyl CHCH 214-216 S 2-ethoxy-5 bromophenyl (CH.,.);--- 193 6Z-n-propyloxy-ibromophenyl CH CH 208-210 7 2-methoxy-5-bromophenyl CHCH, 218-220 EXAMPLE 84,6-Diamino-1,2-dihydro-2,2-dimethyl-l(3-trifluoromethylbenzyloxy)- l,3,5-triazine hydrochloride A mixture of4,6-diamino-l,2-dihydro-2,2-dimethyl-lhydroxy-l,3,5-triazinehydrochloride (3.87 g.) in methanol (60 ml.) containing 1.4 g. potassiumhydroxide was refluxed for 20 minutes and then evaporated under vacuum.The residual solid, suspended in 50 ml. dimethylformamide, was treatedwith 3.8 g. m-trifluoromethylbenzyl chloride and stirred for 24 hours atroom temperature. The mixture was filtered and the filtrate evaporatedto give 3.77 g. solid, m.p. 198 200 after washing with acetone. Washingwith water and crystallization of the insoluble material from ethanolgave 2.1 g. 4,6-diamino-1,2-dihydro-2,2-dimethyl-l-(3-trifluoromethylbenzyloxy l ,3 ,S-triazine hydrochloride, m.p. 204 205.

EXAMPLE 9 Tablets of 4,6-diaminol ,2-dihydro-2,2-dimethyll-(2-n-butoxy-S-bromobenzyloxy 1 ,3,5-triazine hydrochloride One tabletcontains 10 mg. of active ingredient. Formulation for production of100,000 tablets (approximately kg.)

Active ingredient 1,000 grams Maize starch (69% moisture limit) 1,500grams Gum. Acacia powder 500 grams Lactose 8,000 grams lcing Sugar 4,500grams Talc 200 grams Magnesium stearate 100 grams Liquid pumflin 15grams Wuter approx. 1 liter NB. 'l'hcoreticul yield 100,000 tabletsMETHOD 1. Granulation 1. Dry starch in a hot air oven at 40 C untilmoisture is reduced to limit of 6 9 percent w/w.

2. Sieve each of the powders separately through a 40 mesh sieve.

3. Place the active ingredient in a planetary mixer and gradually addthe lactose with continual stirring.

4. Add the icing sugar, starch and acacia, mixing for about 5 minutesafter each addition, continue to mix for a further 20 minutes.

5. With constant mixing, add sufficient water until a suitable granuleconsistency is obtained (approximately 1 liter).

6. Pass damp granules through a rotary granulator fitted with a 10 meshscreen.

7. Dry the granules on trays at approximately C.

2. Compression mixture 1. Pass the dried granules through a 16 meshscreen.

2. Sieve sufi'icient dried granules on a 40 mesh sieve to obtainapproximately 500 grams of fines.

3. Mix the liquid parafiin with the fines and pass through a 20 meshsieve.

4. Pass the tale and magnesium stearate through a 20 mesh sieve.

5. To the bulk of the granules in a planetary mixer add the lubricatedfines, followed by the talc and magnesium stearate. Mix thoroughly forat least 10 minutes after each addition, and finally for 20 minutes. i3. Tabletting Compress the tablets on a rotary machine using specifiedpunches and limits of thickness.

' Check weight of tablets 10 tablets weigh 1.5 gms. N.B. Coating Tabletscan be spray coated with specified film coating lacquer.

I claim:

l. A compound selected from the group consisting of a substitutedtriazine of the formula:

Nay INE.

to each other to form a spirocycloalltane group or a lower alkylspirocycloalkane group including the 2-carbon atom of the triazine ring,the spirocycloalkane group having five seven carbon atoms, an acid saltthereof or an acid addition salt thereof.

2. A compound selected from the group consisting of a substitutedtriazine of the formula:

where Ar is: phenyl substituted by alkoxy of one 24 carbon atoms andhalogen, R, is:

hydrogen or lower alkyl of one four carbon atoms, R is:

lower alkyl of one four carbon atoms where R, and R, are individuallythe same or different or together joined to each other to form aspirocycloalkane group or a lower alkyl spirocycloalkane group includingthe 2-carbon atom of the triazine ring, the spirocycloalkane grouphaving five seven carbon atoms,

' and a pharmaceutically acceptable acid addition salt thereof.

3. A compound as claimed in claim 2 in which Aris benzene substituted bya lower alkoxy group of onesix carbon atoms and by a halogen atom.

4. A compound as claimed in claim 3 in which Ar is2-alkoxy-5-halogenophenyl.

5. A compound selected from the group consisting of 4,6- diaminol,2-dihydro-2,2dimethyll-( Z-n-butoxy-S- bromobenzyloxy)- l ,3,5-triazineand a phannaceutically acceptable salt thereof.

6. A compound as claimed in claim 1 in which Ar is benzene substitutedby a single halogenoloweralkyl group.

7. A compound as claimed in claim 6 in which Ar is benzene substitutedby a trifluoromethyl group.

8. A compound as claimed in claim 7 in which Ar is 3-trifluoromethylphenyl.

9. A compound as claimed in claim I in the form of an acetyl derivative.

# l t i i

2. A compound selected from the group consisting of a substitutedtriazine of the formula: where Ar is: phenyl substituted by alkoxy ofone - 24 carbon atoms and halogen, R1 is: hydrogen or lower alkyl ofone - four carbon atoms, R2 is: lower alkyl of one - four carbon atomswhere R1 and R2 are individually the same or different or togetherjoined to each other to form a spirocycloalkane group or a lower alkylspirocycloalkane group including the 2-carbon atom of the triazine ring,the spirocycloalkane group having five - seven carbon atoms, and apharmaceutically acceptable acid addition salt thereof.
 4. A compound asclaimed in claim 2 in which Ar is benzene substituted by a lower alkoxygroup of one - six carbon atoms and by a halogen atom.
 4. A compound asclaimed in claim 3 in which Ar is 2-alkoxy-5-halogenophenyl.
 5. Acompound selected from the group consisting of4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2-n-butoxy-5-bromobenzyloxy)-1,3,5-triazine and a pharmaceutically acceptable salt thereof.
 6. A compoundas claimed in claim 1 in which Ar is benzene substituted by a singlehalogenoloweralkyl group.
 7. A compound as claimed in claim 6 in whichAr is benzene substituted by a trifluoromethyl group.
 8. A compound asclaimed in claim 7 in which Ar is 3-trifluoromethylphenyl.
 9. A compoundas claimed in claim 1 in the form of an acetyl derivative.